1. Field of the Invention
The invention relates to a novel method of producing fused ring based compounds or aromatics including aminosterol compounds. A method of the invention offers regioselective oxidation and regioselective sulfonation of fused ring systems with few protecting groups. The aminosterol compounds produced by a method of the invention are useful as, among others, antibiotics, antiangiogenic agents and NHE3 inhibitors.
2. Description of the Related Art
Several aminosterol compositions have been isolated from the liver of the dogfish shark, Squalus acanthias. One important aminosterol is squalamine (3β-(N-[3-aminopropyl]-1,4-butanediamine)-7α, 24R-dihydroxy-5α-cholestane 24-sulfate), illustrated FIG. 1. The aminosterol squalamine, which includes a sulfate group at the C-24 position, is the subject of U.S. Pat. No. 5,192,756 which also describes the aminosterol's antibiotic properties.
Since the discovery of squalamine, however, several other interesting properties of this compound have been discovered. For example, as described in U.S. Pat. Nos. 5,733,899 and 5,721,226, squalamine may function as an antiangiogenic agent useful for the treatment of cancers. See U.S. Pat. No. 6,147,060. Additional uses of squalamine such as an agent for inhibiting NHE3 and as an agent for inhibiting endothelial cell growth are disclosed in U.S. Pat. No. 5,792,635.
Methods for synthesizing squalamine have been described. See WO 94/19366 which relates to U.S. patent application. Ser. No. 08/023,347. U.S. Pat. No. 5,792,635 also discloses squalamine isolation and synthesis techniques.
Stemming from the discovery of squalamine, other aminosterols have been discovered in the dogfish shark liver and have been investigated. One important aminosterol that has been isolated and identified as “compound 1436” or simply “1436” has the structure shown in FIG. 2. This compound has the general molecular formula C37H72N4O5S and a calculated molecular weight of 684.53017. Like squalamine, this aminosterol has a sulfate group at the C-24 position.
Compound 1436 previously has been described in U.S. Pat. No. 5,795,885. As further described in this patent, compound 1436 has a variety of interesting properties. For example, compound 1436 inhibits human T-lymphocyte proliferation, as well as the proliferation of a wide variety of other cells and tissues. Additional uses of compound 1436 are disclosed in U.S. Pat. No. 6,143,738. U.S. Pat. Nos. 5,795,885 and 5,847,172 also describe the structure of compound 1436 as well as processes for synthesizing and isolating the compound. For example, compound 1436 can be prepared from a squalamine starting material.
Difficulties have been encountered, however, when attempting to provide a process for synthesizing squalamine or compound 1436 from commercially available starting materials (i.e., not from shark liver isolates). These difficulties include low overall yields of the desired steroid product as well as multiple synthetic steps.
Additional difficulties are encountered in providing a sulfate group at the C-24 position. Particularly, it is difficult to provide the sulfate group at the C-24 position in a highly stereoselective orientation. See, for example, Pechulis, et al., “Synthesis of 24R-Squalamine, an Anti-Infective Steroidal Polyamine,” J. Org. Chem., 1995, Vol. 60, pp. 5121-5126; and Moriarty, et al., “Synthesis of Squalamine. A Steroidal Antibiotic from the Shark,” Tetrahedron Letters, Vol. 35, No. 44, (1994), pp. 8103-8106.
Because of the importance of squalamine, compound 1436, other aminosterols, 24R and 24S-hydroxylated steroids and vitamin-D3 metabolites, there has been considerable interest in preparing stereospecific compounds especially at the C-24 position. As mentioned above, processes for producing squalamine and compound 1436 have been described. However, these processes do not enable large scale production of the desired aminosterol compounds because relatively low yields are realized by these processes.
Processes for stereoselectively producing cerebrosterol, MC 903, and 1α, 24(R)-dihydroxyvitamin D3 have been developed. Koch, et al., “A Stereoselective Synthesis and a Convenient Synthesis of Optically Pure (24R)- and (24S)-24 hydroxycholesterols,” Bulletin de la Société Chimique de France, 1983, (No. 7-8), Vol. II, pp. 189-194; Calverley, “Synthesis of MC 903, a Biologically Active Vitamin D Metabolite Analogue,” Tetrahedron, 1987, Vol. 43, No. 20, pp. 4609-4619; and Okamoto, et al. “Asymmetric Isopropylation of Steroidal 24-Aldehydes for the Synthesis of 24(R)-Hydroxycholesterol, Tetrahedron: Asymmetry, 1995, Vol. 6, No. 3, pp. 767-778. These processes attempt to reduce 22-ene-24-one and 22-yne-24-one systems in a stereoselective manner. Unfortunately, the processes were not highly stereospecific and often resulted in mixtures of the 24R and 24S which were difficult to separate. Thus these processes were not conducive to large scale synthesis.
Other attempts were also not conducive to large scale synthesis. These processes suffered from being too lengthy or impractical. For example, successful reduction has been achieved of a related 25-ene-24-one system using Noyor's 2,2′-dihydroxy-1,1′-binaphthyl lithium aluminum hydride reagent at −90° C. to give 95:5 selectivity for the 24R-alcohol. Ishiguro, et al. “Stereoselective Introduction of Hydroxy-Groups into the 24-, 25-, and 26-Positions of the Cholesterol Side Chain,” J. C. S. Chem. Comm., 1981, pp. 115-117. However, the 25-ene-24-one intermediate material producible in four steps) is less readily accessible than the 22-ene-24-one system (producible in one step). Furthermore, the low temperature required for the chiral reduction also detracts from the commercial practicality of this method.
A large scale stereoselective synthesis has been developed to satisfy the requirements for rapid entry in Phase I clinical trials. Zhang, X., et al., J. Org. Chem., 63, 8599-8603 (1998). However, the synthesis suffered two major drawbacks. First, the synthesis was quite lengthy. Secondly, introduction of a 7α-hydroxyl group proved problematic.
Thus there exists a need in the art for a method of preparing aminosterol compounds such as squalamine, compound 1436 and various homologs that overcome the drawbacks of prior synthetic methods.